Mild Recessive Bullous Congenital Ichthyosiform Erythroderma due to a Previously Unidentified Homozygous Keratin 10 Nonsense Mutation Akiko Tsubota,

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Mild Recessive Bullous Congenital Ichthyosiform Erythroderma due to a Previously Unidentified Homozygous Keratin 10 Nonsense Mutation Akiko Tsubota, Masashi Akiyama, Jean Kanitakis, Kaori Sakai, Toshifumi Nomura, Alain Claudy, Hiroshi Shimizu Journal of Investigative Dermatology Volume 128, Issue 7, Pages 1648-1652 (July 2008) DOI: 10.1038/sj.jid.5701257 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 The patient's clinical features. (a and b) Clinical features at birth. (a) The patient showed generalized erythroderma and blisters. (b) Superficial erosions were seen on the neck and chest. (c and d) At the age of 3 years, the patient had verrucous, hyperkeratotic plaques, from light to dark brown in color, and superficial erosions on the chest, abdomen (c) and the back (d). (d, inset) A superficial denuded area in the hyperkeratotic skin (maserung phenomenon)-like erosion on the back. Journal of Investigative Dermatology 2008 128, 1648-1652DOI: (10.1038/sj.jid.5701257) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Granular degeneration, clumped keratin filaments, and keratin expression patterns in the patient's epidermis. (a) Hyperkeratosis and granular degeneration with large keratohyalin granules were noted in the uppermost spinous and the granular layers of the patient's epidermis. Bar=50μm. (b) Electron microscopic examination of the superficial epidermal keratinocytes revealed a large number of keratin filament clumps (arrows) only in the uppermost spinous and granular layer cells. Inset: high-power view of a keratin clump. Bars=2.5μm (inset, 0.6μm). (c) Immunohistochemically, no staining is observed with an anti-K10 antibody, suggesting absence of K10 in the patient's epidermis. Bar=50μm. (d) K5/K6 brown labeling is observed in the whole epidermis of the patient's skin, with a maximal intensity in the basal cell layer. Bar=50μm. Journal of Investigative Dermatology 2008 128, 1648-1652DOI: (10.1038/sj.jid.5701257) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 A homozygous dinucleotide substitution mutation c.1281_1282CC>AA in KRT10 was detected in the patient. (a) Direct sequencing of KRT10 exon 6 PCR products revealed that the patient was a homozygote for the dinucleotide substitution mutation c.1281_1282CC>AA, whereas both her parents were heterozygous for the same mutation. (b) Mutant allele-specific amplification (MASA) analysis. With normal allele-specific primers, no amplification band was seen in the PCR product from the patient's DNA samples, suggesting that she had no normal allele. With mutant allele-specific primers, the amplification band from the mutant alleles was detected as a 197bp fragment only in the PCR product from the DNA sample from the patient, but not in the PCR product from control DNA samples, confirming the presence of the mutation c.1281_1282CC>AA in the patient. Journal of Investigative Dermatology 2008 128, 1648-1652DOI: (10.1038/sj.jid.5701257) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 The truncation mutation sites of K10 in the recessive form of BCIE. The nonsense mutation detected in the present family is marked with red characters. The other, previously reported nonsense mutation in exon 6 lead to mRNA decay (Müller et al., 2006). By the present mutation, the downstream domain (from the dotted line) was not translated, probably resulting in mRNA decay, because the present mutation was upstream of the previous mutation in the same exon 6 (Lejeune and Maquat, 2005). Red areas: helix initiation or termination motif. Journal of Investigative Dermatology 2008 128, 1648-1652DOI: (10.1038/sj.jid.5701257) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions